The female sex hormones estradiol and estrone are involved in many physiological processes and have been studied extensively. The formation of these steroids is regulated by a number of enzymes. The enzyme aromatase is the rate limiting enzyme in the conversion of testosterone and androstenedione to estradiol and estrone. As disclosed in U.S. Pat. No. 4,322,416, granted 30 Mar. 1982, certain 10-alkynyl steroids that can regulate or inhibit aromatase may have the potential to treat clinical conditions which are potentiated by the presence of estrogens. Aromatase inhibitors have been used for the treatment of conditions such as gynecomastia, male infertility associated with oligospermia, fertility control, endometrial cancer associated with production of high levels of estrogens, and most importantly, for treatment of breast cancer.
Breast cancer is one of the leading causes of death in women in the United States. About two-thirds of breast cancers are hormone independent and are treated with radiation or chemotherapy. The remaining one-third are hormone-dependent and are treated with either endocrine ablative therapy, or with the antiestrogen tamoxifen, or with aromatase inhibitors.
Aromatase inhibitors have also been shown to be effective as second line therapeutic agents in tamoxifen resistant breast cancer. In March 1996, the FDA approved the first Type II aromatase inhibitor for use in the United States. Other nonsteroidal aromatase inhibitors are currently being evaluated for safety and efficacy. The steroidal aromatase inhibitor, 4-hydroxyandrostenedione, has been approved in the United Kingdom for treatment of breast cancer. Aromatase inhibitors are currently recognized as useful tools for the management and remission of metastatic breast cancer. Therefore, there is a need for effective aromatase inhibitors to treat breast cancer and other cancers.